This invention relates to a device for transdermal administration of an active pharmaceutical at a sustained, substantially uniform rate of delivery over an extended period of time. More particularly, the invention relates to a device particularly adapted for transdermal administration of verapamil.
Treatment of patients with pharmaceutically active substances is commonly carried out by periodically adminstering defined doses of the pharmaceutical to the patient, e.g. either orally or by injection. Such techniques provide a maximum dosage of the pharmaceutical following each administration which then continually declines until the next dose is administered. In order to assure that an effective dosage of pharmaceutical is present in the body at all times, peak dosages which are much higher than the effective level are needed. This undesirably increases the amount of pharmaceutical which is consumed and concomitantly increases the danger of undesired side effects. Moreover, even though substantial excess dosages are adminstered, there is always a danger that the concentration of the pharmaceutical may drop below the effective level if adminstration of a subsequent dose is delayed or omitted. Further, there is a possibility, particularly with oral administration of pharmaceuticals, that a portion of the pharmaceutically active substance may be metabolized before reaching its intended locus of activity. This further increases the excess of pharmaceutical which must be administered in order to assure that an effective concentration is maintained.
Techniques also exist for sustained, low level administration of pharmaceuticals. The technique most commonly utilized is intravenous infusion. This technique, while effective at providing sustained low levels of pharmaceutical, is cumbersome and also requires close supervision by trained medical personnel. Consequently, intravenous infusion of pharmaceuticals typically requires hospitalization of the patient with attendant expense and inconvenience.
Techniques have also been developed for administering pharmaceuticals at sustained low levels by absorption through the skin. Transdermal delivery devices are now commercially available for nitroglycerin, scopolamine and other pharmaceuticals. Such devices typically comprise either a pharmaceutical-containing reservoir enclosed by a membrane through which the pharmaceutical can diffuse at a controlled rate or a dispersion of pharmaceutical in a polymer matrix from which the pharmaceutical can diffuse at a controlled rate. The devices are attached either adhesively or otherwise to the skin of a patient, and the pharmaceutical is permitted to diffuse from the device and permeate through the outer sublayers of skin until it is absorbed into the blood stream in the fine capillary network of the dermis. Once absorbed into the blood stream, the pharmaceutical is then carried throughout the entire body system of the patient.
While such transdermal delivery devices have worked well for some pharmaceuticals, notably nitroglycerine, conventional transdermal delivery devices have not proved suitable for other important drugs. Reservoir-type delivery devices are subject to the risk of undersirable dose damping if the rate controlling membrane is inadvertently damaged. The rate of release of some pharmaceuticals from conventional devices has proved to be too slow to provide an effective dosage of pharmaceutical unless the size of the transdermal delivery patch was excessively large. In some instances it has been difficult to maintain effective contact between the transdermal drug delivery device and the skin of the patient. Attempts to solve the problem of maintaining contact by providing an adhesive over the face of the delivery device so that it positively adheres to the patient's skin have not been fully successful. In some instances, due to the nature of the drug delivery matrix, available adhesives have not adhered well to the transdermal drug delivery device. Where satisfactory adhesion between the drug delivery device and the matrix has been obtained, it has been found that the adhesive acts as a barrier and retards transfer of the active substance from the drug delivery device to the skin. For some pharmaceuticals, the rate of skin permeation and absorption is so low that it has not been possible to provide an effective dosage within a reasonably sized area of skin.
One drug for which a transdermal delivery device would be desirable is 5-[(3,4-dimethoxy-phenethyl) methyl-amino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile, also known as verapamil. This substance is a well established coronary vasodialator and antiarrythmic agent. A self-supporting polymeric diffusion matrix for sustained transdermal delivery of verapamil has been proposed by Keith et al. (PCT application No. WO83/00091), but this system is subject to many of the disadvantages discussed above.